This P-RCE brings together the strengths of 77 researchers, both basic and clinical and from both Universities and Industry, in the states of Minnesota, Illinois, Michigan, Indiana, and Ohio. Administrative infrastructure for this application includes leadership at each one of the institutions involved. Our research strengths are in Basic Biology of Category A agents of Bioterrorism, Inhalation Biology and Host Response to Category A organisms, Diagnostics and Experimental Therapeutics, and Vaccine Evaluation, the latter where we have two premier organizations committed to participate. We are particularly interested in moving basic research into clinical application. We submit two R01s and several concept projects in these areas. The first R01 seeks funding to study a novel two-component regulatory system in Bacillus anthracis that in other Gram-positive bacteria is essential to virulence. We have shown that the regulatory system homologue exists in B. anthracis and have initiated studies to clone and insertionally inactivate the system. Furthermore, we hypothesize that this regulatory system is the target of compounds that we have identified and inhibit production of exotoxins. The second R01 provides an example of our strength in Inhalation Biology with a project to study the mechanism underlying Francisella tularensis entry and trafficking into macrophages, and the role surfactant plays in these processes. Concept projects complement these studies and initiate research into Category A viral agents. We anticipate that in 1-2 years these grants will develop into 3-4 program projects. In addition, we have assembled a team of highly-skilled leaders to train both present and future researchers in the safe handling of Category A agents; we have a large collective number of BSL3 facilities to achieve this training, combined with a well-conceived plan. Finally, we have begun development of seamless interactions with first-line emergency responders in all Region V states, with our intent to serve as overflow "Bench Workers" if bioterrorism events occur.